1. Field of Invention
The present invention relates to an improved process for the preparation of crosslinked polyallylamine. More specifically the present invention relates to a process for crosslinking of aqueous polyallylamine dispersed in an organic medium so as to maximize the yield of crosslinked product in the desired particle size range of 60 to 100 mesh.
2. Background of the Technology
Polyallylamine is a polymer of allylamine. The amine group of the polymer can be functionalized further. The polymer finds a wide range of applications such as flocculants, coatings and additives. It is well known that the monomer mono allyl amine does not polymerize readily as it undergoes degradative chain transfer. Allylamine is therefore converted into its salt such as hydrochloride or sulfate and polymerized in the presence of a free radical initiator. The polymerization of salts of allylamine is described adequately in U.S. Pat. Nos. 6,303,723, 6,787,587, 6,579,933, 6,509,013, 6,083,495, 5,667,775, 5,496,545, which are cited herein by way of reference.
Polyallylamine hydrochloride solutions are then partly neutralized and crosslinked using a wide range of crosslinking agents described in U.S. Pat. Nos. 6,509,013, 6,083,495, 5,667,775, 5,496,545, 4,605,701, which are cited herein by way of reference. The crosslinkers typically used are epichlorohydrin, 1,4 butane diol diglycidyl ether, 1,2 ethane diol diglycidyl ether, 1,3 dichloropropane, 1,2 dichloroethane, succinyl dichloride, dimethyl succinate and toluene diisocyanate. More specifically the partly neutralized polymer of allylamine hydrochloride is crosslinked using epichlorohydrin.
The use of crosslinked polymer for binding phosphates and bile acids is disclosed in U.S. Pat. Nos. 5,496,545, 6,667,775, 6,083,495, 6,509,013, 6,696,087, 6,433,026, 6,423,754, 6,294,163, 6,203,785, 6,190,649, 6,083,497, 6,066,678, 6,060,517, 5,981,693, 5,925,379, 5,919,832, 5,969,090, 5,917,007, 5,840,766, 5,703,188, 5,679,717, 5,607,669.
The crosslinked polymers are formulated in tablets as described in U.S. Pat. Nos. 6,696,087 and 6,733,780. The methods of making phosphate binding polymers for oral administration are described in U.S. Pat. Nos. 6,509,013, 6,083,495, 5,496,545, 5,667,775, more particularly the U.S. Pat. Nos. 5,496,545, 5,667,775, 6,083,495, 6,509,013, 4,605,701, which are cited herein by way of reference.
According to the teaching of the U.S. Pat. No. 6,083,495, the method of crosslinking involves reacting for about 15 minutes polyallylamine with a difunctional crosslinking agent in an aqueous solution as to form a gel and allowing the gel to cure for 18 hours at room temperature. The gel is then fragmented into gel particles in a blender in the presence of isopropanol. The gel particles are then washed repeatedly with water and then suspended in isopropanol, filtered and dried in vacuum oven for 18 hours.
The process of crosslinking in aqueous solution described in above patents, leads to gelation. Curing at room temperature takes a long time. The gel is difficult to break into gel particles and needs application of high shear in special equipments. The gel particles swell when repeatedly extracted with water and need to be treated with isopropanol again prior to drying. The process also consumes large excess of water and isopropanol. The gel particles need to be dried in a vacuum oven for long time.
This is because polymeric gels adhere to each other and equipment surfaces. In order to overcome problems associated, drying is carried out in presence of additives, which are either azeotrope forming solvents or agents which influence surface wetting of the gel particles. The U.S. Pat. No. 6,600,011 describes the spray drying technique for drying of crosslinked polyallylamine, which is claimed to avoid damage to shear sensitive polymer gels, and also enables improved particle size control. The patent also describes the use of a Ystral three stage disperser to achieve the desired particle size.
Drying of the aqueous slurry by spray drying , needs careful control of the feed pressure and temperature. Especially the feed temperature depends on the nature of the feed in that the feed temperature has to be below the glass transition temperature of the hydrogel and needs to be so adjusted as not to degrade the hydrogel. The U.S. Pat. Nos. 6,362,266 and 6,180,754 describe a process for producing a crosslinked polyallylamine polymer having reduced cohesiveness. According to the teachings of the said patents the crosslinking reaction is carried out in a specially designed reactor, which can handle highly viscous solutions and can break the gel into small pieces after gelation. Typically a LIST-Discotherm B reactor is suitable for carrying out the crosslinking reaction which generates easy to handle clumps of gel. The application of high shear is detrimental as it leads to the formation of soluble oligomers.
The dried crosslinked polymer is further ground using a mortar and pestle, a Retsch mill or a Fritz mill. The patents further describe that during the drying stage the hydrogel becomes highly cohesive, which leads to high power consumption to rotate the agitator. The addition of a surfactant is recommended to reduce the cohesiveness during drying. In summary, the crosslinking of polyallylamine in aqueous solution leads to gelation. The gel is then fragmented in blenders into gel particles, which are then treated with water and isopropanol and then dried. It is also reported that the application of high shear contributes to soluble oligomers, which are undesirable. Hence methods have been proposed to minimize the oligomer content in the final product. Also the use of specific equipments like LIST Discotherm B reactor has been suggested for carrying out crosslinking and spray driers for drying the crosslinked polymers. Especially spray drying is a critical operation in that the feed temperature has to be below the glass transition temperature of the crosslinked polymer.
The existing methods of crosslinking polyallylamine polymer need specialized equipments for converting the gel into gel particles and /or drying the gel particles formed.
The polyallylamine hydrochloride salt used for crosslinking in the present invention is reported extensively in the literature. More specifically the synthesis of the polyallylamine hydrochloride polymer is disclosed in the U.S. Pat. Nos. 6,083,495, 5,667,775, 5,496,545, 6,303,723, 4,605,701, 6,509,013, the disclosures of which are incorporated herein by reference.
The polyallylamine hydrochloride polymer used for crosslinking is partly neutralized prior to crosslinking. This is achieved by dissolving the polymer in water and by adding a calculated amount of alkali such as sodium hydroxide or potassium hydroxide either as a solid or as an aqueous solution.
U.S. Pat. No. 6,362,266 reports ion exchange, dialysis nano filtration or ultrafiltration as methods to remove the salt. In the crosslinking processes described in U.S. Pat. Nos. 6,509,013, 5,496,545, 5,667,775, 6,083,495 the salts are removed by extraction with water after the crosslinked polyallylamine polymer obtained in the form of gel is fragmented into gel particles by treatment with isopropanol in a blender. This process involves the treatment of gel mass in blenders in presence of solvents and is not easy to operate.
The process described by the present invention leads to the formation of gel particles, which can be more readily washed either with an organic solvent or water in order to extract the salts. Furthermore, the gel particles formed as a result of the process described herein, do not readily agglomerate and hence can be washed with water and solvent readily and can also be dried more easily.
The crosslinking agents used for the crosslinking of the polyallylamine hydrochloride are extensively described in the U.S. Pat. Nos. 6,362,266, 6,509,013, 5,496,545, 5,667,775, 6,083,495. In the above patents, the crosslinking agent is added to the partly neutralized polyallylamine hydrochloride at room temperature and the crosslinking reaction is allowed to proceed as such. In contrast, according to the procedure described in this invention, it is desirable to cool the neutralized polyallylamine hydrochloride solution in the range 4° C.-10° C. prior to the addition of the crosslinking agent so that the polymer solution does not undergo substantial crosslinking before the dispersion of the aqueous solution into the organic medium is complete and the dispersion of the aqueous phase in the organic phase is readily achieved. The dispersion of the aqueous phase comprising partly neutralized polyallylamine hydrochloride salt and crosslinking agent, in an organic medium is more readily achieved by incorporating a suitable surfactant such as SPAN 85 in the organic medium.
According to the teaching of the U.S. Pat. Nos. 5,667,775, 5,496,545, 6,083,495, 6,509,013, the aqueous polyallylamine solutions to which the crosslinking agent is added, gel in about 15 minutes and the gel is then allowed to cure for 18 hrs at room temperature. The gel is then broken into pieces by putting into a blender with isopropanol. While this treatment can be carried out on the scales described in these patents, these operations are more difficult to carry out on large scales. U.S. Pat. No. 6,362,266 describes the use of LIST-Discotherm B reactor to process high viscosity materials and break the gel into small gel particles.
According to the method of the present invention, the polymer solution containing the crosslinking agent is dispersed in an organic medium before substantial crosslinking takes place. Since the polymer solution is crosslinked in individual liquid droplets to form gel particles, which are suspended in an organic phase, the viscosity of the resulting dispersion is much lower than the viscosity of gel formed when crosslinking is carried out according to the methods previously reported in the literature. The crosslinking of polyallylamine hydrochloride as described herein can be readily carried out in conventional batch reactors provided with stirrers commonly used in the chemical industry.
U.S. Pat. No. 4,605,701 describes the use of chlorobenzene and dichlorobenzene as an organic solvent and a non ionic surfactant sorbitane sesquioleate. However, the use of chlorinated hydrocarbons is being discouraged in view of the environmental damage caused by the chlorinated hydrocarbons. Also high boiling points of solvents such as chlorobenzene and dichlorobenzene render the removal of solvents from the polymer difficult. Accordingly the present invention envisages the use of non chlorinated solvents as organic medium.
Further, the above patent claims the crosslinked homopolymer of monoallylamine having a particle size not more than 2 mm. However, the said patent does not deal any further with the particle size and its distribution and more particularly the importance of the particle size in relation to the properties and applications of the polymer in phosphate binding.
In a surprising development the inventors of the present invention have observed that the phosphate binding capacity of the crosslinked polyallylamine hydrochloride, which is indicative of the ability of the crosslinked polymer to bind with the phosphates in the body, also depends upon the particle size of the dried product. The crosslinking of the polyallylamine hydrochloride in the dispersion medium results in a distribution of the particle sizes. The coarse particles exhibit a lower phosphate binding capacity. The finer particles exhibit a higher phosphate binding capacity. While the coarse particle generated during the process can be further ground to yield product in the desired size range in 60-100 mesh, the grinding process also produces fines, which pass through a 100 mesh sieve. While the phosphate binding capacity of the fines is not significantly different than the particles in the size range 60-100 mesh, the fines are not particularly suitable for the preparation of tablets. It is therefore desirable that the crosslinking of polyallylamine hydrochloride be carried out under conditions wherein the particle size of the crosslinked product produced in the reactor is in the range 60-100 mesh, so that no further processing is required.
There is therefore a need to develop a method for the synthesis of crosslinked polyallylamine which will simplify the manufacturing method, minimize the need for specialized equipments, bring down the need for wash solvents and will thus bring down the manufacturing costs.
According to the method of the present invention, the crosslinking is carried out in the dispersion medium in the presence of a suitable surfactant and the choice of the stirrer and stirring speed such that the yield of the crosslinked product in the size range 60-100 mesh is maximized. If the yield of the product which passes through the 100 mesh sieve and which is retained over 60 mesh sieve is minimized, only a small portion of the product of the reactor will have to be subjected to size reduction and the loss of fines will also be minimum.